The invention is directed to biodegradable, thermoplastic, phase separated segmented multiblock copolymers, and the use thereof as delivery vehicle, in particular for biologically active agents such as proteins and peptides. The copolymers of the present invention find use in various biomedical as well as pharmaceutical applications.
Generally, thermoplastic phase separated co-polymers consist of a low glass transition temperature (Tg), flexible ‘soft’, amorphous, segment and a high Tm (semi)crystalline ‘hard’ segment which are incompatible or only partially compatible.
Examples of phase separated segmented/block copolymers are found e.g. in U.S. Pat. Nos. 6,255,408, 5,554,170, 5,066,772, 5,236,444, 5,133,739 and 4,429,080. These known materials are bioresorbable co-polyesters wherein the hard blocks are predominantly built of crystalline poly-glycolide and/or poly-lactide. Glycolide rich polyesters are especially suitable for fast resorbable biomedical articles such as mono- or multi filament sutures; L-lactide rich polyesters are used in more slowly resorbing medical applications, such as nerve guides, nerve graft and many other products. However, the high melting point of the poly-glycolide or poly-L-lactide rich blocks requires very high polymerisation and processing temperatures (about 200° C.), which may result in unwanted degradation behavior and/or trans-esterification. Furthermore, the poly-glycolide rich polyesters are unsuitable for applications for which a slow resorption is needed.
As an alternative to polyglycolide rich polyesters, poly-L-lactide rich copolyesters have been suggested as materials which have a higher resorption time and very good mechanical properties as a result of the crystalline segments. However, the use of a semi-crystalline random copolymer of L-lactide and ε-caprolactone (50/50) for bridging of peripheral nerve defects and of highly crystalline poly-L-lactide as bone plates have caused some severe problems in the past. Mild to severe foreign body reactions were observed after 2 to 3 years of implantation, respectively, due to the presence of long-lasting biomaterial fragments. (Den Dunnen et al. (Microsurgery 14 (1993) 508-515); Rozema et al. In: P. J. Doherty, R. L. Williams, D. F. Williams, eds. “Biomaterial-Tissue interfaces. Advances in biomaterials” 10 Amsterdam, Elsevier Science Publishers B.V. (1992) 349-355). It is an object of the present invention to provide a new biodegradable, thermoplastic, phase separated segmented multi-block copolymer, which does not suffer from the above-mentioned disadvantages and thus opens possibilities for new medical applications. A further object relates to the provision of a copolymer which is suitably used to encapsulate polypeptides.